The applicant proposes that using pharmacogenetics (i.e., drug prescription based on a patient's genetic background) may dramatically enhance the efficacy of many therapies commonly used in critically ill patients. The PI for this career development award is a trauma/critical care surgeon whose long term research career goal is the application of pharmacogenetic techniques to surgical critical care. As an immediate goal, the PI seeks to develop expertise in molecular genetic techniques essential to this type of translational research. The research proposal, which examines warfarin pharmacogenetics, will provide the framework for achieving the immediate goal through a period of instruction, supervision, and investigation based in a clinical molecular diagnostics laboratory. Like many drugs used in surgical critical care, warfarin has a narrow therapeutic index, an unpredictable dose-response, and untoward interactions with many medications. Despite frequent monitoring, potentially lethal toxicities are common. Current empiric methods of warfarin dosing are inaccurate. Warfarin is metabolized by two distinct subfamilies of the cytochrome P450 complex: CYP2A6 and CYP2C9. Common polymorphisms of these enzymes result in impaired warfarin metabolism. Interindividual variability in warfarin dosing may be attributable to these polymorphisms. The hypothesis is that warfarin dosing based on CYP2C9 and CYP2A6 genotyping will be more accurate and effective than current methods. To address this hypothesis, the applicant will accomplish two Specific Aims. He will (1) determine the frequency of CYP2C9 and CYP2A6 polymorphisms in an ethnically defined population of patients receiving warfarin; and (2) establish the relationship between CYP2C9 and CYP2A6 genotypes and warfarin dose and develop a genetically-based approach to warfarin dosing. The environment for this project is Washington University School of Medicine, an institution with access to a large clinical volume and established expertise in genomic research.